Zafirlukast has the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide. It is known to be practically insoluble in water, slightly soluble in methanol, and freely soluble in tetrahydrofuran, dimethylsulfoxide and acetone.
Zafirlukast is a leukotriene receptor antagonist that blocks the action of cysteinyl leukotrienes on the CysT1 receptors, reducing constriction of the airways, build-up of mucus in the lungs and inflammation of the breathing passages. Zafirlukast is commercially available, for example under the brand name ACCOLATE™, and is commonly used to treat asthma.
The use of zafirlukast to treat skin disorders has also been disclosed, both by oral and topical treatment methods. Topical treatments have the advantage of delivering the active pharmaceutical ingredient only to those areas in need of such treatment.
U.S. Pat. No. 6,440,994 claims a method of treating skin disorders such as acne vulgaris, acne rosacea, acne conglobata and hidrandenitis suppurativa by administering a therapeutically effective amount of a leukotriene receptor antagonist such as zafirlukast. An oral treatment method is disclosed.
WO 1999032125 claims a pharmaceutical composition comprising at least one leukotriene antagonist (e.g., zafirlukast) and at least one antihistamine. A method is also claimed for treating diseases of the skin by administering the pharmaceutical composition to a mammal. Skin diseases include atopic dermatitis, psoriasis and chronic idiopathic urticaria. Preferably, the pharmaceutical composition is designed for oral administration.
WO 2005089761 claims a pharmaceutical composition containing a combination of a leukotriene receptor antagonist (e.g., zafirlukast) and a histamine H3 receptor ligand. A method is claimed for treating an H3 mediated disease and/or a leukotriene mediated disease by administering the pharmaceutical composition. A method for treating dermatitis is claimed. Topical administration to the skin is disclosed. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
WO 2005089748 claims a pharmaceutical composition containing a combination of a leukotriene receptor antagonist (e.g., zafirlukast) and a histamine H receptor ligand. A method is claimed for treating an H4 mediated disease and/or a leukotriene mediated disease by administering a pharmaceutical composition comprising an effective amount of a leukotriene antagonist and an effective amount of a histamine H4 receptor antagonist. A method for treating dermatitis is claimed. Topical administration to the skin is disclosed. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
US 2011/0124681 discloses a method of treating dermatological conditions by administering a topical formulation comprising at least one leukotriene antagonist, e.g., zafirlukast. The “dermatological conditions” include wrinkling of the skin, eczema, uneven texture of the skin, hyperpigmentation, and scarring caused by conditions such as acne, including adult rosacea, or “adult acne.” Preferred topical dosage forms include aerosols, gels, solutions, lotions, creams, ointments and foams. Topical ointment formulations are disclosed, which may variously comprise petrolatum, zinc oxide, vegetable oils, animal fats, semisolid hydrocarbons obtained from petroleum, hydroxystearin sulfate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol, glyceryl monostearate, lanolin, polyalkylsiloxanes, stearic acid, and/or polyethylene glycols of varying molecular weight. Additional active components may include additional active agent, excipients, solvents, emulsifiers, chelating agent, surfactants, emollients, permeation enhancers, preservatives, antioxidants, lubricants, pH adjusters, adjuvants, dyes, and perfumes. The Example discloses a topical formulation comprising zafirlukast, propylene glycol, ethanol, water and glycerin.
G. Riccioni et al. have reviewed the use of leukotriene receptor antagonist drugs in diseases in which leukotrienes play a pathogenic role. It is noted that several studies documented that combined therapy with montelukast and zafirlukast produced significantly greater improvements than placebo or cetirizine monotherapy in the treatment of chronic urticaria. (“Advances in Therapy with Antileukotriene Drugs,” Annals of Clinical & Laboratory Science, vol. 34, no. 4, 2004, pp 379-387)
J. A. Bernstein et al. assessed the antagonism of LTD4-induced cutaneous vascular reaction in man by ICI-204,219 (zafirlukast). They state that it is believed that leukotrienes may participate in the pathogenesis of nonallergic and allergic cutaneous diseases. They also note that it remains to be demonstrated whether an LTD4 antagonist, such as ICI-204,219 (zafirlukast), will have clinical use for management of selected cases of urticaria or psoriasis. (“The effect of the oral leukotriene antagonist, ICI-204,219, on leukotriene D4 and histamine-induced cutaneous vascular reactions in man,” J. Allergy Clin. Immunol., January 1991, pp 93-98)
J. A. Carruci et al. disclose treatment of atopic dermatitis using oral administration of zafirlukast. (“The Leukotriene Antagonist Zafirlukast as a Therapeutic Agent for Atopic Dermatitis,” ARCH DERMATOL., Vol. 134, July 1998, pp 785-786)
E. J. Dabowski et al. also disclose the treatment of atopic dermatitis with oral zafirlukast. (“Treatment of atopic dermatitis with zafirlukast,” Dermatology Online Journal, 5 (2), https://escholarship.org/uc/item/589055t9)
Topical formulations are typically most effective when the pharmaceutical agent is soluble in the formulation. Although zafirlukast is known to be soluble in solvents such as tetrahydrofuran, dimethylsulfoxide and acetone, such solvents are typically not recommended or are contraindicated for use in topical formulations because of concerns for toxicity and/or volatility. There remains, therefore, a need for a safe and effective zafirlukast-containing composition for treating dermatological conditions.